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Shear-induced Notch-Cx37-p27 axis arrests endothelial cell cycle to enable arterial specification

Author

Listed:
  • Jennifer S. Fang

    (Yale University School of Medicine
    Yale University School of Medicine
    Yale University School of Medicine
    Yale University School of Medicine)

  • Brian G. Coon

    (Yale University School of Medicine
    Yale University School of Medicine
    Yale University School of Medicine)

  • Noelle Gillis

    (Yale University School of Medicine
    Yale University School of Medicine
    Yale University School of Medicine
    Yale University School of Medicine)

  • Zehua Chen

    (WuXi NextCODE 55 Cambridge Parkway)

  • Jingyao Qiu

    (Yale University School of Medicine
    Yale University School of Medicine
    Yale University School of Medicine
    Yale University School of Medicine)

  • Thomas W. Chittenden

    (WuXi NextCODE 55 Cambridge Parkway
    Boston Children’s Hospital, Harvard Medical School
    Massachusetts Institute of Technology)

  • Janis M. Burt

    (College of Medicine, The University of Arizona)

  • Martin A. Schwartz

    (Yale University School of Medicine
    Yale University School of Medicine
    Yale University School of Medicine
    Yale University School of Medicine)

  • Karen K. Hirschi

    (Yale University School of Medicine
    Yale University School of Medicine
    Yale University School of Medicine
    Yale University School of Medicine)

Abstract

Establishment of a functional vascular network is rate-limiting in embryonic development, tissue repair and engineering. During blood vessel formation, newly generated endothelial cells rapidly expand into primitive plexi that undergo vascular remodeling into circulatory networks, requiring coordinated growth inhibition and arterial-venous specification. Whether the mechanisms controlling endothelial cell cycle arrest and acquisition of specialized phenotypes are interdependent is unknown. Here we demonstrate that fluid shear stress, at arterial flow magnitudes, maximally activates NOTCH signaling, which upregulates GJA4 (commonly, Cx37) and downstream cell cycle inhibitor CDKN1B (p27). Blockade of any of these steps causes hyperproliferation and loss of arterial specification. Re-expression of GJA4 or CDKN1B, or chemical cell cycle inhibition, restores endothelial growth control and arterial gene expression. Thus, we elucidate a mechanochemical pathway in which arterial shear activates a NOTCH-GJA4-CDKN1B axis that promotes endothelial cell cycle arrest to enable arterial gene expression. These insights will guide vascular regeneration and engineering.

Suggested Citation

  • Jennifer S. Fang & Brian G. Coon & Noelle Gillis & Zehua Chen & Jingyao Qiu & Thomas W. Chittenden & Janis M. Burt & Martin A. Schwartz & Karen K. Hirschi, 2017. "Shear-induced Notch-Cx37-p27 axis arrests endothelial cell cycle to enable arterial specification," Nature Communications, Nature, vol. 8(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01742-7
    DOI: 10.1038/s41467-017-01742-7
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    Cited by:

    1. Jonas Stewen & Kai Kruse & Anca T. Godoi-Filip & Zenia & Hyun-Woo Jeong & Susanne Adams & Frank Berkenfeld & Martin Stehling & Kristy Red-Horse & Ralf H. Adams & Mara E. Pitulescu, 2024. "Eph-ephrin signaling couples endothelial cell sorting and arterial specification," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    2. Susanne Fleig & Tamar Kapanadze & Jeremiah Bernier-Latmani & Julia K. Lill & Tania Wyss & Jaba Gamrekelashvili & Dustin Kijas & Bin Liu & Anne M. Hüsing & Esther Bovay & Adan Chari Jirmo & Stephan Hal, 2022. "Loss of vascular endothelial notch signaling promotes spontaneous formation of tertiary lymphoid structures," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. Jan-Renier Moonen & James Chappell & Minyi Shi & Tsutomu Shinohara & Dan Li & Maxwell R. Mumbach & Fan Zhang & Ramesh V. Nair & Joseph Nasser & Daniel H. Mai & Shalina Taylor & Lingli Wang & Ross J. M, 2022. "KLF4 recruits SWI/SNF to increase chromatin accessibility and reprogram the endothelial enhancer landscape under laminar shear stress," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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